TAZ在乙醛诱导股骨头坏死中BMSCs分化失衡的作用研究

Alcohol was believed as the main contributor to the development of alcohol-induced osteonecrosis,during which the role of acetaldehyde, the most important metabollite of alcohol, was rerely reported. Our preliminary results show that acetaldehyde can induce the imbalance between BMSCs osteogenesis and adipogenesis as well as remarkably reduce the level of TAZ mRNA, which indicats TAZ inhibition may correlate with the enhance of osteogenesis and impairment of adipogenesis. Acetaldehyde-induced TAZ inhibition may play a critical role in alcoholic osteonecrosis. Therefore, this project intends to further clarify the role of TAZ in acetaldehyde-induced imbalance of BMSCs differentiation by TAZ gene overexpression, silence and fluorescent tracer technique. With new animal model of acetaldehyde induced osteonecrosis and stem cell implantation , the role of TAZ in the disease will be explored and validated in vivo.Then the signaling of TAZ will be clarified combined with the role of TAZ. This study will contribute to understanding the pathogenesis of alcoholic osteonecrosis, from the perspective of cell differentiation and provide new potential targets for personalized prevention and treatment of osteonecrosis.

既往对酒精性股骨头坏死的机制研究主要集中在乙醇的毒性作用，而乙醛作为酒精体内代谢后的重要存在形式，其对骨质损伤及BMSCs分化的研究鲜见报道。我们前期发现乙醛能干扰BMSCs成骨/成脂分化的平衡，且显著性降低BMSCs细胞分化中关键因子TAZ的转录水平。这些结果提示，乙醛对TAZ的抑制可能是乙醛诱导成骨活性降低、成脂增强，进而导致股骨头坏死的关键步骤。因此，本项目拟通过慢病毒载体的构建上调或下调TAZ的表达水平，解析TAZ在乙醛诱导的BMSCs由成骨向成脂分化转换中的作用；并结合新的乙醛诱导小鼠股骨头坏死模型及干细胞移植，探讨TAZ在疾病动物模型中的潜在治疗作用；最后，结合TAZ的关键作用，进一步阐明其作用的关键信号途径。本研究将有助于从新的干细胞分化角度认识酒精性股骨头坏死的发病机制，进而为该病的个性化预防和治疗提供新的思路。